This is a 371 of PCT/FR00/00865 filed Apr. 6, 2000.
The present invention relates to the use of tianeptine, of isomers thereof and of salts thereof, in obtaining medicaments intended for the treatment of neurodegenerative pathologies.
Tianeptine, the compound of formula (I): 
has been described in French Patent Specification FR 2 104 728 as a new medicament for use in the treatment of psychoneurotic disorders, pain and cough.
Furthermore, French Patent Specification FR 2 635 461 describes the use of tianeptine and compounds thereof in the treatment of stress.
Recent studies have shown that tianeptine has significant effects on memory. These are described by:
S. E. FILE et al. in: Drug Development Research, 1991, 23, 47-56;
R. Jaffard et al. in: Journal de Psychiatrie Biologique et Thxc3xa9rapeutique, 1989, March special edition, 37-39;
R. Jaffard et al. in: Abstracts of the XVIth CINP Congress, Munich (Germany), 15-19, August 1988; Psychopharmacology, 1988, 96 (suppl), 31.02.32, p. 275;
R. Jaffard et al. in: Behavioural Pharmacology, 1991, 2, 37-46;
C. Lebrun et al. in: European Psychiatry, 1993, 8 (suppl. 2), 81s-88s;
R. Jaffard et al. in: Presse Mxc3xa9dicale, 1991, 20, 37, 1812-1816.
Finally, French Patent Specification FR 2 716 623 describes the use of the (+) isomer of tianeptine in obtaining medicaments intended for mnemo-cognitive disorders.
The Applicant has now discovered, surprisingly, that tianeptine is a modulator of glutamate receptors of the AMPA/kainate type and may therefore be used in the treatment of neurodegenerative pathologies.
L-glutamic acid and L-aspartic acid are capable of activating the neurons of the central nervous system, and numerous studies have demonstrated that these excitatory amino acids (EAAs) meet the defining criteria of a neurotransmitter; for this reason, modulation of the neuronal events associated with those EAAs appears to be a promising target for the treatment of neurological diseases.
Indeed, it has been proven that the excessive release of EAAs and hyperstimulation of their receptors could be one of the causes of the neuronal degeneration that is observed in epilepsy, senile dementia or cerebral vascular accidents. At the present time, the number of neurodegenerative diseases in which EAAs are strongly implicated is continually growing (Huntington""s chorea, schizophrenia, amyotrophic lateral sclerosis) (Mc GEER E. G. et al., Nature, 263, 517-519, 1976; SIMON R. et al., Science, 226, 850-852, 1984).
Moreover, even though hyperactivation of EAA neurotransmission certainly produces neurotoxic effects, normal activation thereof facilitates mnemic and cognitive performance (LYNCH G. and BAUDRY M., Science, 224, 1057-1063, 1984; ROTHMAN S. M. and OLNEY J. W., Trends in Neuro Sci., 10, 299-302, 1987). From the pharmacological and therapeutic point of view, it is therefore appropriate to combat pathological stimulation only, whilst maintaining the level of physiological activation.
EAA receptors having a post- and pre-synaptic location have been classified into 4 groups as a function of the affinity for and electrophysiological and/or neurochemical effects of specific ligands:
the NMDA (N-methyl-D-aspartate) receptor, which is associated with an ion channel that is permeable to mono- and di-valent cations (including calcium) but blocked by magnesium. Accumulation of calcium and zinc in the cell might be one of the causes of neuron death. Opening of the NMDA channel is regulated by several sites associated with the receptor and, in particular, is facilitated by glycine, the effect of which is strychnine-insensitive. That glycine site represents an important target for modulating activation of the NMDA receptor.
the AMPA (xcex1-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) receptor, which is associated with an ion channel that is permeable to monovalent cations, including sodium. Activation of this channel might bring about membrane depolarisation.
the kainate receptor, the ionic characteristics of which are similar to those of the AMPA receptor but differ therefrom in the levels of conductance and desensitisation. Numerous studies tend to prove, however, that the AMPA receptor and the kainate receptor have close structural and functional analogies and constitute a single receptor family (KEINANEN K. et al., Science, 249, 556-560, 1990).
the ACPD (trans-1-aminocyclopentane-1,3-dicarboxylic acid) receptor, which is called the metabotropic receptor because it is not coupled to an ion channel.
Activation of the ionotropic receptors by EAAs opens the ion channels and especially allows the entry of sodium, which depolarises the cell. That first phase, which involves the AMPA receptor, then leads to disinhibition and, after that, hyperactivation of the NMDA receptor and massive accumulation of calcium (BLAKE J. F. et al., Neurosci. Letters, 89, 182-186, 1988; BASHIR Z. I. et al., Nature, 349, 156-158, 1991).
It has more especially been shown that tianeptine, in a novel manner, modulates the glutamatergic receptors of the AMPA/kainate type and could therefore be used in the treatment of neurodegenerative pathologies.
More specifically, the present invention relates to the use of tianeptine, enantiomers thereof and pharmaceutically acceptable salts thereof in obtaining pharmaceutical compositions intended for the treatment of neurodegenerative pathologies, such as cerebral ischaemia, cerebral traumatism, cerebral ageing, Alzheimer""s disease, multiple sclerosis, amyotrophic lateral sclerosis, demyelinating pathologies, encephalopathies, chronic fatigue syndrome, myalgic encephalomyelitis, post-viral fatigue syndrome, the state of fatigue and depression following a bacterial or viral infection, and the dementia syndrome of AIDS.
Tianeptine and enantiomers thereof, optionally in the form of pharmaceutically acceptable salts, shall be presented in pharmaceutical forms that are suitable for administration by the oral, parenteral, per- or trans-cutaneous, nasal, rectal, perlingual, ocular or respiratory route, especially injectable preparations, aerosols, eye or nose drops, sublingual tablets, glossettes, soft gelatin capsules, hard gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels etc., those forms allowing the immediate release or delayed and controlled release of the active ingredient.
The dosage varies according to the age and weight of the patient, the administration route, the nature of the therapeutic indication and associated treatments, and ranges from 12.5 mg to 300 mg per dose or per administration.
As bases that may convert tianeptine or enantiomers thereof into salts, there may be used, without implying any limitation, sodium hydroxide, potassium hydroxide, calcium hydroxide or aluminium hydroxide, alkali metal or alkaline earth metal carbonates, or organic bases such as triethylamine, benzylamine, diethanolamine, tert-butylamine, dicyclohexylamine, arginine etc.
As acids that may convert tianeptine or isomers thereof into salts, there may be used without implying any limitation, hydrochloric acid, sulphuric acid, phosphoric acid, tartaric acid, malic acid, maleic acid, fumaric acid, oxalic acid, methanesulphonic acid, ethanesulphonic acid, camphoric acid, citric acid etc.
The preferred salt of tianeptine is the sodium salt.